Glycogen accumulation and phase separation drives liver tumor initiation

Qingxu Liu; Jiaxin Li; Weiji Zhang; Chen Xiao; Shihao Zhang; Cheng Nian; Junhong Li; Dongxue Su; Lihong Chen; Qian Zhao; Hui Shao; Hao Zhao; Qinghua Chen; Yuxi Li; Jing Geng; Lixin Hong; Shuhai Lin; Qiao Wu; Xianming Deng; Rongqin Ke; Jin Ding; Randy L Johnson; Xiaolong Liu; Lanfen Chen; Dawang Zhou

doi:10.1016/j.cell.2021.10.001

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Glycogen accumulation and phase separation drives liver tumor initiation

Journal article

Peer reviewed

Glycogen accumulation and phase separation drives liver tumor initiation

Qingxu Liu, Jiaxin Li, Weiji Zhang, Chen Xiao, Shihao Zhang, Cheng Nian, Junhong Li, Dongxue Su, Lihong Chen, Qian Zhao, …

Cell, Vol.184(22), pp.5559-5576.e19

10/28/2021

DOI: https://doi.org/10.1016/j.cell.2021.10.001

PMID: 34678143

Abstract

cancer initiation

glycogen storage

Hippo signaling

liver cancer

Mst1

Mst2

phase separation

Glucose consumption is generally increased in tumor cells to support tumor growth. Interestingly, we report that glycogen accumulation is a key initiating oncogenic event during liver malignant transformation. We found that glucose-6-phosphatase (G6PC) catalyzing the last step of glycogenolysis is frequently downregulated to augment glucose storage in pre-malignant cells. Accumulated glycogen undergoes liquid-liquid phase separation, which results in the assembly of the Laforin-Mst1/2 complex and consequently sequesters Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme-liver glycogen phosphorylase (PYGL) deficiency in both human and mice results in glycogen storage disease along with liver enlargement and tumorigenesis in a Yap-dependent manner. Consistently, elimination of glycogen accumulation abrogates liver growth and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that cancer-initiating cells adapt a glycogen storing mode, which blocks Hippo signaling through glycogen phase separation to augment tumor incidence. [Display omitted] •Cancer-initiating cells adapt glycogen storage state to improve survival•Downregulation of G6PC augments glycogen storage and cell transformation•Accumulated glycogen undergoes phase separation to suppress Hippo signaling•Elimination of glycogen accumulation abrogates cancer incidence Accumulated glycogen undergoes liquid-liquid phase separation to suppress Hippo signaling and drive liver tumor initiation.

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Title: Glycogen accumulation and phase separation drives liver tumor initiation
Creators: Qingxu Liu - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Jiaxin Li - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Weiji Zhang - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Chen Xiao - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Shihao Zhang - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Cheng Nian - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Junhong Li - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Dongxue Su - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Lihong Chen - Department of Pathology, School of Basic Medical Sciences of Fujian Medical University, Fuzhou, Fujian 350004, China
Qian Zhao - Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai 200433, China
Hui Shao - School of Biomedical Sciences and School of Medicine, Huaqiao University, Quanzhou, Fujian 362021, China
Hao Zhao - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Qinghua Chen - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Yuxi Li - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Jing Geng - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Lixin Hong - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Shuhai Lin - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Qiao Wu - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Xianming Deng - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Rongqin Ke - School of Biomedical Sciences and School of Medicine, Huaqiao University, Quanzhou, Fujian 362021, China
Jin Ding - Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, Shanghai 200433, China
Randy L Johnson - Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
Xiaolong Liu - The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, The Liver Center of Fujian Province, Fuzhou 350025, P.R. China
Lanfen Chen - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Dawang Zhou - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Publication Details: Cell, Vol.184(22), pp.5559-5576.e19
Publisher: Elsevier Inc
Identifiers: 9924050701701921
Academic Unit: Department of Biology; Rosenstiel Basic Medical Sciences Research Center
Language: English
Resource Type: Journal article

Glycogen accumulation and phase separation drives liver tumor initiation

Abstract

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